(161f) The Impact of Spacer Length on the Morphology and Internalization of MUC1 Aptamer-Amphiphile Nanoparticles for Targeting and Imaging Triple Negative Breast Cancer Cells

Few targeted treatment options exist for triple negative breast cancer (TNBC), leaving only chemotherapy and radiation treatments with poor response and high off-target toxicity. To address this crucial need for targeted therapy, single-stranded DNA aptamer‐amphiphiles were synthesized which selectively bind to the mucin‐1 (MUC1) glycoprotein that is overexpressed in TNBC cells. These amphiphiles have a fluorescent, hydrophobic tail (1,8‐naphthalimide or 4‐nitro‐1,8‐naphthalimide) which allows for easy visualization and enables self-assembly. This tail is attached to the aptamer via an alkyl spacer (C₄ or C₁₂) whose length was shown to influence the morphology of the self‐assembled structure, and thus its ability to internalize into the TNBC cells. While both the MUC1 aptamer‐C₄‐napthalimide spherical micelles and the MUC1 aptamer‐C₁₂‐napthalimide long cylindrical micelles showed internalization into MDA‐MB‐468, SUM159, and MDA-MB-231 TNBC cells, but not the normal MCF‐10A breast cells, the cylindrical micelles showed greatly enhanced internalization. In addition, a pharmacokinetic study in mice showed a prolonged systemic circulation time of the MUC1 aptamer cylindrical micelles. There was a 4.6‐fold increase in the elimination half‐life of the aptamer cylindrical micelles, and their clearance decreased 10‐fold compared to the MUC1 aptamer spherical micelles. Given the clear advantages of the cylindrical micelles, their ability to act as a drug delivery vehicle was characterized. The MUC1 aptamer cylindrical micelles by themselves were not toxic to the cells, however, when used to deliver doxorubicin to the TNBC cells, were shown to be as cytotoxic as free doxorubicin. Thus, the MUC1 aptamer‐C₁₂‐napthalimide nanofibers represent a promising vehicle that could be used for easy visualization and targeted delivery of therapeutic loads to TNBC cells.